DESCRIPTION (the applicant's description verbatim): Current evidence indicates that unopposed estrogen replacement therapy (ERT) reduces cardiovascular morbidity and mortality. In part, the cardioprotective effects of oral estrogen are believed to be due to a) alteration of lipid transport pattern, b) ERT-induced effects on lipid transport not totally reflected by measurement of cholesterol and triglyceride levels, and/or c) non-lipid effects of ERT. Although previous studies have shown that ERT has beneficial effects on presumptive risk factors for cardiovascular disease (CVD) in postmenopausal women, these studies have yielded limited information concerning these effects directly on the actual atherosclerosis process because of the absence of arterial imaging endpoints. In short, the univariate associations of ERT on lipid and non-lipid endpoints, as well as the multivariate associations of ERT, lipid and non-lipid endpoints on the atherosclerosis process in postmenopausal women are poorly understood. We plan to address these issues with a recently completed randomized, double-blind, placebo-controlled, carotid artery ultrasonographic ERT trial in 221 healthy postmenopausal women 46 to 80 years old without CVD symptoms (primary prevention). The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) provides a unique opportunity to evaluate the association of lipid and non-lipid factors of unopposed ERT-mediated reduction in the progression of subclinical atherosclerosis in healthy postmenopausal women under conditions which eliminate self-selection and differential interaction with the medical care system. In EPAT, unopposed ERT significantly reduced the rate of change of carotid artery intima-media thickness (IMT) as compare to placebo. By determining the effects of ERT on putative CVD risk factors in postmenopausal women and linking these effects to arterial wall change in carotid IMT, we will be able to study the effects of ERT directly on the progression of subclinical atherosclerosis. Specifically, we plan to study the effects of ERT on regulation of lipoprotein metabolism with standard lipid measures as well as with measures beyond the traditional cholesterol and triglyceride lipid measurements, the thrombotic/thrombolytic system, LDL oxidation, and carbohydrate, homocysteine and nitric oxide metabolism, and a variety of clinical measures. Because the clinical trial phase of EPAT is completed, a very large and rich database is available at considerable savings. Since 90 percent of coronary deaths of women occur after menopause, elucidating the effects by which unopposed ERT reduces the progression of subclinical atherosclerosis in healthy postmenopausal women has important public health implications for the prevention of CVD in postmenopausal women.